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Structure of 6089-04-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 6089-04-9 |
Formula : | C8H12O2 |
M.W : | 140.18 |
SMILES Code : | C#CCOC1CCCCO1 |
MDL No. : | MFCD00006604 |
InChI Key : | HQAXHIGPGBPPFU-UHFFFAOYSA-N |
Pubchem ID : | 98609 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H225 |
Precautionary Statements: | P210-P403+P235 |
Class: | 3 |
UN#: | 1993 |
Packing Group: | Ⅲ |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.75 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 38.79 |
TPSA ? Topological Polar Surface Area: Calculated from |
18.46 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.26 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.05 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.24 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.16 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.83 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.51 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.24 |
Solubility | 8.09 mg/ml ; 0.0577 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.03 |
Solubility | 13.1 mg/ml ; 0.0937 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.98 |
Solubility | 14.7 mg/ml ; 0.105 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.41 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.6 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With copper(l) iodide; palladium 10% on activated carbon; triethylamine; triphenylphosphine; In 1,4-dioxane; at 25 - 80℃; for 3.5h;Inert atmosphere; | General procedure: (a) The reaction was performed in a bigger scale using 100 mg of 10% Pd/C (0.092 mmol), PPh3 (0.37 mmol), CuI (0.184 mmol), Et3N (10.68 mmol), compound 1a (3.56 mmol), and acetylenic compound 2a (5.32 mmol) in 1,4-dioxane (20.0 mL). After stirring at 80 C for 3 h under nitrogen the mixture was cooled to room temperature. The Pd/C was filtered off and washed with water (2 10 mL), acetone (2 10 mL), and EtOAc (2 10 mL). Then the catalyst was collected, dried at 100 C in an oven, and reused for the next run. The co-catalyst CuI along with PPh3 was added in every repeated run. (b) General method for the preparation of 3: A mixture of compound 1 (0.89 mmol), 10% Pd/C (0.023 mmol), PPh3 (0.092 mmol), CuI (0.046 mmol), and Et3N (2.67 mmol) in 1,4-dioxane (5.0 mL) was stirred at 25 C for 30 min under nitrogen. The acetylenic compound 2 (1.33 mmol) was added slowly with stirring. The mixture was then stirred at 80 C for 3 h, cooled to room temperature, diluted with EtOAc (30 mL), and filtered through celite. The filtrate was collected and concentrated. The residue was purified by column chromatography (2-15% EtOAc/hexane) to afford the desired product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In tetrahydrofuran; water; at 20℃; for 48h;Inert atmosphere; | M. Synthesis of (6S)-6-({1-methyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}methoxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (11) by the method of Scheme 8 A solution of 2-(2-propynyloxy)tetrahydro-2H-pyran (69) (0.758 g, 5.41 mmol), CuI (17 mg, 0.09 mmol) and PdCl2(PPh3)2 (0.158 g, 0.023 mmol) in THF (15 mL) was purged with N2. 1-Iodo-4-(trifluoromethoxy)benzene (70) (1.30 g, 4.51 mmol) in THF (10 mL) was added, followed by a solution of methylhydrazine sulfate (1.95 g, 13.5 mmol) and NaHCO3 (2.27 g, 27 mmol) in water (25 mL). The mixture was flushed with carbon monoxide and then stirred at room temperature for 2 days under one atmosphere of carbon monoxide. The resulting mixture was partitioned between CH2Cl2 and water, the CH2Cl2 fraction was dried, and the solvent was evaporated. Column chromatography of the residue on silica gel (eluting with CH2Cl2) gave 1-methyl-5-[tetrahydro-2H-pyran-2-yloxy)methyl]-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazole (71) (1.034 g, 64%) as a brown solid: mp 40-42 C.; 1H NMR (CDCl3) δ 7.78 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 6.51 (s, 1H), 4.75 (d, J=12.8 Hz, 1H), 4.69 (t, J=3.3 Hz, 1H), 4.57 (d, J=12.8 Hz, 1H), 3.94 (s, 3H), 3.84-3.91 (m, 1H), 3.53-3.60 (m, 1H), 1.68-1.88 (m, 2H), 1.50-1.66 (m, 4H). APCI MS m/z 357 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In tetrahydrofuran; at 100.0℃; for 0.5h;Inert atmosphere; Microwave irradiation; | Nitrogen was bubbled through a solution of Ethyl 5-bromo-2-phenylthiazole- 4-carboxylate (3.6 g, 11.5 mmol) and 2-(prop-2-ynyloxy)tetrahydro-2H-pyran (3.3 rnL, 23.1 mmol) in THF (30 mL). Dichlorobis(triphenylphosphine)palladium (II) (405 mg, 0.6 mmol), copper (I) iodide (55 mg, 0.3 mmol), and triethylamine (TEA) (8 mL, 57.7 mmol) were added and the reaction mixture was heated at 1000C for 30 min in a microwave reactor. The reaction mixture was poured into H2O and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by MPLC eluting with pentane/EtOAc (0-50% gradient) to give ethyl 2-phenyl-5-(3-(tetrahydro-2H-pyran-2-yloxy)prop-l- ynyl)thiazole-4-carboxylate (3.8 g, 88 % yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With copper(l) iodide; sodium hydrogencarbonate;bis(triphenylphosphine)palladium(II) dichloride; In tetrahydrofuran; water; at 20℃; for 48h; | A solution of 2-(2-propynyloxy)tetrahydro-2/J-pyran (69) (0.758 g, 5.41 mmol), CuI (17 mg, 0.09 mmol) and PdCl2(PPh3)2 (0.158 g, 0.023 mmol) in THF (15 mL) was purged with N2. l-Iodo-4-(trifiuoromethoxy)benzene (70) (1.30 g, 4.51 mmol) in THF (10 mL) was added, followed by a solution of methylhydrazine sulfate (1.95 g, 13.5 mmol) and NaHCO3 (2.27 g, 27 mmol) in water (25 mL). The mixture was flushed with carbon monoxide and then stirred at room temperature for 2 days under one atmosphere of carbon monoxide. The resulting mixture was partitioned between CH2Cl2 and water, the CH2Cl2 fraction was dried, and the solvent was evaporated. Column chromatography of the residue on silica gel (eluting with CH2Cl2) gave 1 -methyl-5-[(tetrahydro-2//-pyran-2-yloxy)methyl]-3-[4-(trifluoromethoxy)phenyl]-lH-pyrazole (71) (1.034 g, 64%) as a brown solid: mp 40-42 0C; 1H NMR (CDCl3) δ 7.78 (d, J = 8.8 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 6.51 (s, 1 H), 4.75 (d, J = 12.8 Hz, 1 H), 4.69 (t, J= 3.3 Hz, 1 H), 4.57 (d, J- 12.8 Hz, 1 H), 3.94 (s, 3 H), 3.84-3.91 (m, 1 H), 3.53-3.60 (m, 1 H), 1.68-1.88 (m, 2 H), 1.50-1.66 (m, 4 H). APCI MS m/z 357 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | <strong>[303-49-1]Clomipramine</strong> 2 (0.503 g; 1.43 mmol; 1 equiv) was mixed with Cs2CO3 (1.13 g; 3.57 mmol; 2.5 equiv) and XPhos precatalyst PdG1 (0.0313 g; 0.0428 mmol; 3 mol %) in a glove box. To this anhydrous acetonitrile (4 mL) was added, and the reaction mixture was left with stirring, in the glove box for 25 min before THP protected propargyl alcohol (0.501 g; 3.57 mol; 2.5 equiv) was added. The reaction vessel was sealed, removed from the glove box, and then heated to 80 C for 20 h. After 20 h the reaction mixture was cooled to rt and quenched with saturated NaHCO3 (aq). The mixture was extracted with AcOEt, and the combined organic phases were dried over MgSO4, filtered and evaporated. The product was purified by column chromatography (first CH2Cl2/CH3OH 50:1 then CH2Cl2/CH3OH 20:1). Upon repeated column chromatography, the product was isolated as brown oil in 63% yield (0.375 g; 0.895 mmol). Rf (CH2Cl2/CH3OH 20:1) 0.45. 1H NMR (400 MHz, CDCl3) deltaH 7.16-7.02 (m, 4H), 6.99 (s, 2H), 6.94 (dt, 1H, J = 7.3, 1.1 Hz), 4.88 (t, 1H, J = 3.4 Hz) 4.46 (q, 2H, J = 15.7 Hz), 3.93-3.81 (m, 1H), 3.77 (t, 2H, J = 6.6 Hz), 3.61-3.50 (m, 1H), 3.12 (s, 4H), 2.60 (t, 2H, J = 5.6 Hz), 2.35 (s, 6H), 1.96-1.48 (m, 8H). 13C NMR (100 MHz, CDCl3) deltaC 147.9, 134.9, 134.4, 130.3, 129.7, 126.7, 125.9, 123.3, 123.2, 120.7, 120.4, 96.9, 86.0, 84.4, 62.1, 57.3, 54.9, 48.5, 44.9, 32.6, 31.8, 30.4, 25.5, 19.2 ppm. HRMS (ES+): Calcd for C27H34N2O2H: 419.2699; found 419.2699. |
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